Drug-Eluting Coatings Applied To Medical Devices By Spraying And Drying To Remove Solvent

ABSTRACT

A coating device for coating a medical device with a drug-eluting material uses an in-process drying station between coats to improve a drug release profile. The drying station includes a heat nozzle configured for applying a uniform drying gas. A coating process using the dryer includes a closed-loop control for the gas between drying steps and an improved nozzle for producing more consistent spray patterns.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to drug-eluting medical devices; moreparticularly, this invention relates to processes for controlling theinteraction among polymer, drug and solvent, and the release rate of adrug for drug eluting medical devices.

2. Background of the Invention

Strict pharmacological and good mechanical integrity of a drug elutingmedical device are required to assure a controlled drug release.Significant technical challenges exist when developing an effective andversatile coating for a drug eluting medical device, such as a stent.

A coating may be applied by a spray coating process. A drug-polymercomposition dissolved in a solvent is applied to the surface of amedical device using this method. The amount of drug-polymer to beapplied has been expressed as a target coating weight, which correspondsto the weight of the coating after a substantial amount of the solventhas been removed.

It is desirable to obtain better control over the drug-eluting product.Specifically, there is a need to better control the rate of release of adrug, or the effectiveness of a drug when released from the coating. Todate the known prior art has failed to provide adequate solutions.

SUMMARY OF THE INVENTION

The invention improves on the art by providing an apparatus and methodfor forming a drug-eluting coating that offers greater control over therelease rate for a drug and less undesired interaction between a carriersolvent and the drug-polymer matrix. According to the embodiments, aspray nozzle is used to apply the coating material. And a dryer is usedto apply inter-pass drying of coating. The term “inter-pass drying”means drying, or removing solvent between one, two, three or more spraypasses. The weight of material per coat is very light, about 5% of thetotal coating weight according to one embodiment. This means, for thisparticular embodiment, 20 coats are needed to reach 100% of the coatingweight.

Previous efforts to produce a more consistent and stable drug releaseprofile have not been entirely satisfactory. A more precise,controllable/predictable release rate is sought. Efforts to improve uponthe controllability and consistency of the release rate of the drug havefocused on the structure of the polymer, type or structure of thepolymer, and the type of solvent used. However, these improvements havenot been able to satisfactorily meet the needs for certain clinicalapplications, or provide a morphology that can be widely used.

The disclosure includes aspects of both a spraying and drying stepduring the coating of a medical device. The drying aspect will bediscussed first.

A “drug release profile”, or “release profile” means the morphology, orcharacteristics of a drug-eluting matrix that delivers an expectedtherapeutic behavior after being placed within a body. A drug releaseprofile, or release profile therefore informs one of such things as thepredictability of the release rate, variation, if any, in the releaserate over time or on a per unit area basis across a drug-elutingsurface.

It has been discovered that a significant improvement in the ability totailor a drug release profile to suit a particular objective such asproducing a specific release rate, uniformity in the release rate over adrug eluting surface, and/or uniformity in a production setting (highthroughput) lay in obtaining more precise control over the amount ofsolvent present, or rate of solvent removal. The criticality of solventremoval, distribution, etc. generally depends on thedrug-polymer-solvent formulation and particular objectives sought. Whileit is known that the morphology of a drug-polymer matrix is influencedby the presence of a solvent, it was discovered that this interactionplayed a more significant role than previously thought. Based on thisconclusion, a more effective process for controlling the amount ofsolvent-polymer-drug interaction was sought. It was found that thecoating weight per spray cycle and manner in which solvent was removed,in connection with the coating thickness was an important consideration.

A relatively high coating weight per spray cycle has been sought in thepast, because this minimizes process time and increases throughput.Maintaining control over the amount or rate of solvent removal is,however, challenging unless an applied coating layer is relatively thin.If the applied layer is too thick the resistance of the solvent toremoval quickly becomes non-linear and therefore more difficult tocontrol or predict. When the solvent is removed from a thick layer,therefore, the potential for undesired interaction among the solvent,polymer and drug, and related problems begin to impair the ability toretain control over the release profile.

The biocompatibility of the polymer used for a drug eluting medicaldevice, e.g., a stent, is essential. The polymer must benon-inflammatory, capable of being expanded without flaking ordelaminating from the stent, and be able to control the drug release ata predictable rate. Very few polymer systems can meet the requirements.Preferably, EVAL is chosen as a drug matrix material for drug elutingstents. It has shown favorable biological responses. EVAL is asemi-crystalline random copolymer and it is hygroscopic due to itshydroxyl group. The percentage crystallinity of EVAL coating on thestent is dependent on the process conditions (process temperature,humidity, or residual solvent). A solvent (DMAc or DMSO) used todissolve EVAL has a high boiling point. As such, the solvent must beactively removed from the coating, e.g., by heating.

Process conditions can affect the desired morphology. For example, ifthere is excess residual solvent, i.e., solvent not removed between orafter a spray cycle, the solvent can induce a plasticizing effect, whichcan significantly alter the release rate. Therefore, it can becritically important to have a process that produces a coating withconsistent properties—crystallinity, % solvent residue, % moisturecontent, etc. If one or more of these parameters are not properlycontrolled, such that it varies over the thickness or across a surfaceof a drug-eluting device, then the release profile is affected. One ormore of these considerations can be more critical for somedrug-polymer-solvent formulations than for other formulations.

To facilitate the incorporation of a drug on a stent, spraying a lowsolid percent polymer/drug solution over the stent followed by removingthe solvent has become feasible in controlling the amount of drug (inmicrograms range) deposited on the stent and the release profile. It hasnow been discovered that a good coating quality benefits from using thisspray technique, i.e., properties such as the crystallinity, % solventresidue, and % moisture content are more controllable as the coatingweight is built up over several applied coatings. However, a stenthaving tight geometry (to minimize the crimped stent OD size) addssignificant technical challenges to this method. There is a need toremove at least some of the solvent, in an efficient, predictable mannerbetween spray cycles (a spray cycle may include one or more spraypasses, e.g., passing a spray nozzle lengthwise over a rotating stent).In a preferred embodiment, a spray cycle includes one, two, three ormore passes in order to obtain a 5% coating weight in a spray cycle.Ideally one would want to remove all solvent after each coating. It willbe readily understood, however, that this is not a practical solution.Indeed it may not even be possible for solvents having a relatively highboiling point, such as DMAc. Accordingly, even assuming one could removeall, or substantially all solvent between each spray cycle, the need inthe art would not be met because this drying phase would be too timeconsuming.

Previous studies of the drying effect on drug release (EVAL-drug system)indicated a need for an in-process drying technique to remove a solventon the coated stent after each spray cycle. This is a critical step inproducing more stable products while retaining a high throughput.

The properties of a solvent, e.g., surface tension, vapor pressure orboiling point, viscosity, and dielectric constant, used in dissolving apolymer have a dominant effect on the coating quality, coating processthroughput, drug stability, and the equipment required to process it. Asolvent can, of course, be removed by applying a heated gas over thestent. Surprisingly and unexpectedly, however, it was found that thisdrying step must be carefully controlled in order to achieve the desiredend result. A uniform and efficient heat transfer from the gas to thecoating surface must also take place.

The evaporation rate of a suitable solvent has an inverse relationshipwith the coating thickness (generally inversely proportional to thethickness) for a thin film coating. And the resistance increasesnon-linearly as the coating thickness increases. As alluded to earlier,this non-linearity should be avoided. When the thickness is within thelinear range higher efficiency, uniformity and more control is achievedwhen removing the solvent. As a result, a more consistent drug releaseprofile is obtained because there is the least drug-solvent-polymerinteraction, solvent plasticizing and extracting of the drug. It istherefore desired to achieve more control over, not only the uniformityof properties across the thickness, but also the ability to removesolvent. This is because residual solvent on the drug eluting stent mayinduce adverse biological responses, compromise coating properties,induce drug degradation, and alter release profile. The ratiopolymer-to-drug applied during each spray cycle can be 1:1, 2:1, 3:1,4:1 or 5:1.

Thus, it was found that a release rate can be better controlled byapplying many coats of a low percentage solution, e.g., 5% of the finalcoating weight, with a drying step between each spray cycle. Thus, inthis example 20 coats are needed to produce the target coating weight.In order to make this coating process more feasible as aproduction-level method, while maintaining control over the solvent andsolvent-drug-polymer interaction, as just discussed, an efficientin-process drying step was needed.

Dryers

Initial experiments configured a process to include a drying step usinga commercially available air heater having a tubular conduit leading toa flared, or divergent opening. For example, the air heaters with flaredopenings offered by Osram Sylvania™, 131 Portsmouth Ave, Exeter N.H.03833. These types of heaters are typically of metal construction anddirect a gas stream down the tube and into the flared opening, which isinline with the tube. There is a flow-accelerating and re-shapingportion provided by the flared opening. The mean flow direction does notchange as gas travels through the heater.

A flow profile for the gas, i.e., a gas exit velocity from the nozzleand gas temperature, was selected to produce a rapid drying time. It wasexpected that with an appropriate average heat transfer from the gas tothe stent surface using either nozzle, i.e., selecting a suitable dryinggas velocity and temperature, an efficient in process drying stage couldbe incorporated into the coating process, thereby making feasible aprocess of applying many low weight coatings while maintaining controlover the solvent's effects on the drug-polymer morphology. The resultingdrug release profile resulting from the use of the diverging channel orcylindrical nozzle types for solvent removal, did not, however, exhibitthe desired properties. It was hypothesized that more control over theheat transfer might be needed.

Surprisingly and unexpectedly, it was found that when the heat transfercapacity and profile in the gas at the nozzle exit was modified, thatis, made more uniform, there was significant improvement in the abilityto control or tailor a drug release profile to suit the end objective.It was concluded, therefore, that not only is an efficient in-processdrying step needed to produce an improved drug release profile, but alsoa more uniform heat transfer from the gas to the coated surface betweeneach of several applied coatings.

The power or resources expended to remove solvent using a dryer is alsoan important consideration. During a cycling period when a medicaldevice, such as a stent, is being coated, it is desirable to maintainthe flow conditions. However, this can waste resources as expensive gas,such as Nitrogen, is being expended in order to maintain a steady statecondition for the gas. In order to reduce these costs a closed-loopcontrol was devised, which monitors temperature of the gas source atdifferent flow rates. When a dryer is not in use, the head or inlet flowrate is reduced, thereby reducing the mass flow rate (to conserve gas).An increase in temperature of the exiting gas results. A thermocoupleplaced at the entrance to the dryer, and pressure monitor may be inputas control parameters to continuously adjust heating coils to maintainthe same temperature at the input when flow rate is reduced. Bymaintaining the same operating temperature when the gas flow rate isreduced, or the dryer idle, the startup time required to reach steadystate flow is reduced. This provides significant cost savings in bothmaterial and power draw.

The efficiency of a dryer to remove solvent; that is, the amount of gasor energy needed per volume or weight of solvent removed was alsoconsidered. In a preferred embodiment, Nitrogen gas is used for thedrying gas. In an effort to conserve resources, reduce process cyclesand improve the uniformity or consistency of evaporation rates per unitarea over a stent surface the flow properties around the stent wereanalyzed. Initially, it was believed that by placing a stent on amandrel, rotating at a relatively high rate, and near the exit nozzle ofthe dryer all surfaces of the stent would be enveloped continuouslywithin the hot gas and evaporated solvent would be quickly removed.However, it was discovered that the pressure differential between thegas stream exiting the nozzle at a relatively high rate of speed andsurrounding ambient air was high enough to cause significant heat lossand interruption with the flow around the stent. It was found that ifthe pressure of the hot gas were increased in the vicinity of the stent,there was less interference as regards both the heat loss and uniformityof the heat transfer of the hot gas.

Two embodiments of structure designed to increase the efficiency andmaintain uniformity of the gas properties surrounding the stent weredeveloped. The first is a reflector placed behind the stent. thereflector is positioned so that as gas passes over the stent surface, itcollects and maintained within the vicinity of the stent. The resultingpressure increase behind the stent has a tendency to reduce the amountof heat loss caused by the cooler ambient air in the vicinity of thestent.

The second embodiment is a gas expander or skirt positioned over theexit nozzle of the dryer. The gas expander may be a parabolic or conicaltype structure that functions to insulate the low-pressure gas exitingthe nozzle from the cooler ambient air. As the gas passes through theexpanding chamber, the gas is segregated from the ambient air. Itspressure may also increase. In a preferred embodiment, the gas expanderis intended for segregating the hot gas from the surrounding cooler air.However, it will be appreciated that there are other advantages in usinga gas expander according to the invention.

In view of the foregoing, the invention provides one or more of thefollowing additional improvements over the art.

According to another aspect of invention, a method for coating a stentincludes: (a) spraying the stent with a solution comprising 7% coatingby weight and 93% solvent by weight, (b) removing solvent from thecoated stent using a dryer such that following the removing solvent steponly about 8% of the coating by weight is solvent remains in thecoating, and repeating steps (a) and (b) until 100% of a desired coatingweight is reached. Additional steps may include removing solvent fromthe stent between each, or after more than one coating of the solutionis applied by directing a forced mass of gas towards the stent, the gashaving a uniform velocity and temperature profile over the length of thestent wherein substantially only about 8% of the coating weight remainsafter applying the mass of forced gas.

Another aspect of the invention is a method for producing a desiredrelease profile that includes a forced gas drying stage for uniformlyremoving solvent. In a preferred embodiment, solvent is uniformlyremoved for stents having lengths of 20 mm, 100 mm, 150 mm and 200 mm.

Another aspect of the invention is a dryer having an inlet conduitsupplying an incoming gas stream and an exit area that produces a dryinggas. The dryer includes a first gas conditioning chamber and a secondgas conditioning chamber together forming a closed space for theconditioning of a gas supplied by a gas source and discharged at anozzle exit, the gas having a mass flow rate that is the same at thenozzle exit as the mass flow rate supplied by the gas source during asteady state flow condition; the first gas conditioning chamberincluding a circular inlet coupled to the gas source and a linear arrayof apertures downstream of the circular inlet; and the second gasconditioning chamber including the linear array of apertures and anarray of nozzle exit channels downstream of the linear array ofapertures; wherein the dryer is adapted for producing a substantiallyuniform drying air mass from the linear array of nozzle exit channels.

The nozzle exit channels may be configured such that gas passing throughthe channels and exiting from the nozzle is noise reduced by formingvanes at the entrance to the channels, which may reduce the amplitude orfrequency of fluid oscillations at the nozzle exit.

The dryer may further include a gas expander disposed about the lineararray of nozzle exit nozzle channels. The gas expander may be formed bya parabolic or conical skirt that diverges outwardly from the nozzleexit such that gas pressure may decrease as it travels through theparabolic or conical skirt. The dryer may further include, oralternatively have a gas reflector disposed opposite the linear array ofnozzle exit channels.

Another aspect of the invention relates to producing a coating weight byapplying a light layer, drying the layer and then repeating these stepsseveral times until a total coating weight is achieved. The number oflayers can be greater than 19, greater than 30, greater than 40, andbetween 20 and 50 layers. A intermittent or in-process drying step canbe included between each applied layer. The application of layers can bepredetermined or determined by weighing the sprayed medical device andthen continually applying layers until a desired weight is measured.

Another aspect of the invention relates to a heat nozzle for use duringan in-process drying step for coating a drug eluting stent. This heatnozzle may provide a gas curtain with uniform velocity and temperaturedistribution, which improves the uniformity of solvent drying andreduces variability in drug release from the coating.

According to another aspect of invention a closed-loop controller isused to maintain a steady state flow temperature for variable gas flowrates. Using this controller, a dryer gas flow rate may be switchedbetween an idle flow rate when the dryer is not being used andoperational flow rate during a drying stage. As discussed earlier, it isessential that a rate or amount of solvent removal between coats can bepredicted with some degree of certainty. By maintaining an essentiallysteady state flow whenever the stent is being dried, i.e., avoidingtransient flow states, it becomes easier to predict the amount or rateof solvent removal. Moreover, by being able to reduce flow rates duringperiods of non-use, while maintaining a constant gas temperature, gasresources are conserved.

According to another aspect of the invention a method of drying arecently coated stent includes the steps of rotating the stent above anozzle exit portion of a dryer to cause a gas produced by the dryer toeffect a removal rate of solvent from the stent. The gas being producedby the steps of: supplying a gas to the dryer, the gas being deliveredthrough a circular conduit such that the gas has an input mean flowdirection into the dryer, decelerating the gas as it encounters a firstchamber of the dryer, the first chamber presenting the gas with a firstenlarged space arranged such that the gas is expanded in a directionperpendicular to the input mean flow direction, after the gas has beenexpanded in a direction perpendicular to the input mean flow direction,accelerating the expanded gas by forcing the gas through a linear arrayof apertures arranged in the direction perpendicular to the mean flowdirection, the gas entering a second chamber, and decelerating, and thenaccelerating the gas as it fills the second chamber, the second chamberpresenting the gas with a second enlarged space, followed by a narrowedspace downstream of the second enlarged space and the nozzle exitdownstream of the narrowed space. According to this method, the gasproduces a uniform heat transfer from the gas to the stent over theentire surface of the rotating stent. For example, a uniform flow rateof 100 liters/min gas between the ranges of 100 and 120 degrees Celsiusdrying gas may be produced.

According to another aspect of the invention an apparatus for coating astent includes a sprayer for applying a coating to a surface of thestent; and a dryer configured to remove a controlled percentage ofsolvent from a surface of the stent using a stream of gas supplied bythe gas supply. The dryer is an in-process dryer that dries betweencoats.

The dryer may include a first gas conditioning chamber and a second gasconditioning chamber together forming a sealed space for theconditioning of a gas received from a gas source and discharged at anozzle head, the mass flow rate supplied by the gas source being thesame as the mass flow rate at the nozzle head during a steady state flowcondition, the first gas conditioning chamber including a circular inletcoupled to the gas source and a linear array of apertures locateddownstream of the circular inlet, and the second gas conditioningchamber including the linear array of apertures and a line of nozzleexit channels downstream of the linear array of apertures; wherein thefirst gas conditioning chamber and the second gas conditioning chambercooperate to convert gas received at the circular inlet to a gas streamhaving uniform velocity and temperature at the nozzle exit.

The apparatus may further include a control system for controlling therate at which gas is supplied to the dryer and temperature of the gasexiting the dryer such that the gas temperature is maintained at aconstant temperature for variable gas flow rates.

According to another aspect of invention, a method for coating a stentbeing movable between a sprayer and a dryer includes the steps ofproducing a steady state first mass flow rate of a drying gas from anozzle exit of the dryer including the steps of opening a valve andadjusting a heater for heating the gas in response to a sensed change inthe gas temperature; spraying a drug-polymer-solvent on a surface of thestent while the first mass flow rate steady state condition exists atthe nozzle exit; before, or shortly after completing the application ofa first coat of the drug-polymer-solvent on the stent, increasing themass flow rate to the dryer while maintaining the same temperatureincluding the step of adjusting the heater in response to a sensedchange in the gas temperature, the dryer producing a stead state secondmass flow rate; moving the stent to the dryer, or the dryer to thestent, and drying the stent using the gas exiting the dryer at thesteady state second mass flow rate, wherein the second mass flow rate ischaracterized by a uniform, linear heat transfer from the gas to thestent surface such that a correspondingly uniform rate of solventremoval occurs on the stent surface, and the steady state temperature ofthe gas for the first mass flow rate is substantially the same as thesteady state temperature of the gas for the second mass flow rate.

In accordance with another aspect of the invention a dryer may have aratio of the total flux area for the array apertures to the nozzle exitchannels of about 4:1; or the ratio of the total flux area for the arrayapertures to the inlet may be about 1.75:1 or 2:1; or the ratio of thetotal flux area for the nozzle exit channels to the inlet flux area isabout 1:2.

In accordance with another aspect of invention, an array of nozzle exitchannels have a length L, the depth of the combined chambers betweeninlet and exit is D, the height of the combined chambers between inletand exit is H and the size of the diameter at the inlet is 2R, whereinthe ratio of L to D, to H to 2R (L:D:H:2R) is about1:(1/10):(1/3):(1/8); the ratio of L:2R is about 1:8; the ratio of L:Dis about 1:1/10; or the ratio of L:H is about 1:1/3; and wherein thedryer is capable of producing a uniform temperature and velocitysuitable for drying a stent for a flow rate of about 100 liters/min at atemperature in the range of 100 to 120 degrees Celsius.

In accordance with another aspect of invention a dryer exit nozzlelength is sized to minimize variations at the edges of the stent. Thelength of the array of nozzle channels may have a length that is about125% of the length of a stent, or 1.5 times the length of a stent lengthfor which the dryer is configured for drying to produce a uniform heattransfer from the gas to the stent surface.

In accordance with another aspect of invention, a gas expander isconfigured for maintaining a uniform heat transfer near the stentsurface, the stent having a diameter D, wherein the height of theexpander is about four times D, the mouth of the diameter is between twotimes and four times D, and the stent is placed about a D distance fromthe mouth. A gas expander having a height to mouth ratio of 1:1 in someembodiments. In some embodiments, a stent and drying apparatus having amechanism for moving a stent between dryer and sprayer may be configuredfor placing a stent about one stent diameter within the gas expander, orin other embodiments, about a distance of 25% of the height of the gasexpander from the mouth of the expander. The stent may be placed closerto the nozzle exit. In tests conducted using recently coated stents itwas found that an optimal distance was about this 25% (preferably adiameter distance for a 4D×4D gas expander) from the nozzle mouth, whichdistance provided the optimal condition, based on twovariables—stability of stent and efficiency in drying. Thus, accordingto the embodiments an optimal distance, or range is discovered. Theoptimal position of the stent may be found through an optimizationsubject to a constraint of three variables: (1) the type of stentsupport, (2) type of gas expander and nature of the (3) heat transferfrom gas to stent. Parameter (2) is discussed earlier.

Parameter (1) relates to the support used for the stent and, inparticular, the amount of motion allowed when the stent is impacted byfast moving air. In a preferred embodiment, the stent is preferablysupported on a mandrel that provides a loose fit, indeed pseudounstable, to minimize coating defects at surfaces of the stent makingcontact with the mandrel. Examples of mandrels that provide this loosefit are provided in U.S. Pat. No. 7,572,336 and U.S. application Ser.No. 12/554,671. These designs cause the contact points to constantlychange as the stent is rotated, thereby minimizing coating defects. Assuch, the stent is loosely held on the mandrel and therefore moresensitive to high momentum, oscillating, periodic or random gas jostlingof the stent. If the stent was instead held firmly, then the stent maybe placed closely to the nozzle and solvent removed more rapidly (hencegas drying efficiency goes up). However, one then begins to developunacceptable coating defects in the form of bridges, etc. between thestent and mandrel surfaces. Thus, the optimal distance is found byconstraining at least two variables—the size of the gas expander anddegree to which the stent mandrel and stent can sustain random orperiodic loading caused by the exiting gas. Parameter (3) relates to theheat transfer environment. In one embodiment nitrogen gas exiting at arate of 100 liters/min and within the range of 100 to 120 degreesCelsius is chosen in combination with the mandrel described in U.S.application Ser. No. 12/554,671 filed Sep. 4, 2009 (e.g., apparatusshown in FIG. 4 or 7 and description referencing these drawings whichwill be referred to herein as a loose-fitting or instantaneouscontact-type mandrel support, mandrel support that intentionally causeswobbling or relative movement between stent and mandrel when the mandrelis rotated), and the expander dimensions depicted in FIG. 6 to produce adistance of one diameter within the mouth. In other embodiments thestent may be at least one diameter within the mouth, or 25% of theexpander height from the mouth. Additionally, the gas expander sides areformed of heat-insulting PEEK material.

According to another aspect of invention, a method of drying a stent,comprising the steps of dryer having an inlet conduit supplying anincoming gas stream and an exit area that produces a drying gas,comprises placing the stent near an array of nozzle exit channels; andplacing the stent within a gas expander such that the stent is between amouth of the expander and the array of nozzle exit channels; wherein thedryer is adapted for producing a substantially uniform drying air massfrom the linear array of nozzle exit channels. In one particularembodiment, the stent is placed at an optimal distance from the nozzleexit channel, the optimal distance being selected according to theconstraints of the selected dimensions of the gas expander for thestent, the heat transfer properties of the gas including heat loss ratefor exiting gas, and the minimum distance from the nozzle exit to avoidunacceptable jostling or motion of the stent when the stent is beingsupported by loose-fitting mandrel support, or the stent wobbles whenrotated by the mandrel. In one embodiment the distance is one stentdiameter within the mouth for a gas expander with dimensions of 4D×4Dand made of PEEK material, the flow rate is 100 liters/min between100-120 degrees C., and the mandrel supports the stent at non-constantcontact points as the stent rotates, i.e., a wobbling stent-typemandrel.

Spray Nozzles

With the goal of obtaining a more consistent and predictabledrug-release profile over the length of the stent, and obtain improvedefficiency and less wasted resources, the ability of a spray nozzle todeposit a consistent pattern of drug-polymer-solvent was alsoconsidered. Another aspect of invention concerns the uniformity orconsistency of the spray pattern during the spraying step in accordancewith the foregoing need. According to this aspect of invention, there isa method of making a spray nozzle, comprising: forming a housing from afirst metal having a first hardness, the housing including a first borefor the passage of an atomizing gas and a second bore for receivingcannulae, the second bore having a first and second diameter, the firstdiameter forming at its upper end a ledge; forming a cannulae from of asecond metal, the second metal having a second hardness, less than thefirst hardness, the cannulae including a tapered bore for receivingfluid, such that the tapered bore reduces a pressure drop for fluiddisposed within the tapered bore a stepped outer diameter, and apolished lower end; forming a polished nozzle cap that is devoid ofscratches or abrasions on its inner and outer surface near a nozzleorifice; press-fitting the cannulae into the second bore such that thestepped outer diameter is placed against the ledge of the housing bore;and fitting the nozzle at a nozzle exit so that the orifice is alignedwith an exit aperture of the cannulae.

According to another aspect of invention a method for coating a stentwith a drug-polymer solution, comprises spraying the stent using a spraynozzle, including the steps of delivering a first metered supply of anatomizing gas through a first bore in fluid communication with a nozzleorifice, and a drug-polymer solvent fluid through a second bore in fluidcommunication with the nozzle orifice; after spraying the stent, movingthe stent to a dryer for drying the stent; and while the stent is beingdried, applying a second metered supply of a gas to the nozzle, thesecond metered supply being different from the first metered supply,wherein the second metered supply is adapted to reduce instances ofclogging or buildup of drug-polymer solvent proximal the nozzle orificewhen the stent is being dried. The step of while the stent is beingdried, applying a second metered supply of a gas to the nozzle, thesecond metered supply being different from the first metered supply, mayfurther include disposing a second source of pressured gas, external thenozzle, adjacent the nozzle and directed towards the nozzle, andapplying the second metered supply of gas to the nozzle while a thirdmetered supply of gas is applied to the nozzle by way of the secondsource of pressurized gas. The step of disposing a second source ofpressured gas, external the nozzle, adjacent the nozzle and directedtowards the nozzle may further include disposing a second nozzle havinga orifice orientated to direct a stream of gas towards the orifice ofthe nozzle at an angle of between 20-40 degrees relative to a lower faceof the nozzle. The coating applied to the stent may be a solution ofabout 93% solvent and about 7% drug-polymer solution. The solvent may beDMAc.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference, and as if eachsaid individual publication or patent application was fully set forth,including any figures, herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a dryer according to one aspect of thedisclosure. The dryer is supplied a gas through a conduit of a heaterassembly.

FIG. 2A is a top view of the dryer of FIG. 1.

FIG. 2B is a side cross-sectional view of the dryer of FIG. 1 taken atsection AB-2B in FIG. 2A. As depicted here, a gas stream v_(∞) entersthe dryer at an entrance. The gas velocity is abruptly decreased (v₁) asit encounters a wall, at which point it is forced upwardly. Theincreased pressure causes the gas to expand into an upper chamber of aplenum (v₂). Here the high pressure area causes the gas to make anotherright hand turn and exit at higher velocity through a diffuser. The gasin (V1) enters a second chamber. This chamber slows the gas down again,then causes it to accelerate upwardly until it exits from a nozzle exit(v₃). The gas exiting the nozzle is uniform in temperature and velocityand extends over a linear length (gas curtain) for drying a stent (s)disposed over the nozzle.

FIG. 3A is a forwardly looking, exploded assembly view in perspectiveshowing component parts of the dryer of FIG. 1.

FIG. 3B is a close-up view of a portion of a nozzle component of thedryer near the nozzle exit taken from section 3B in FIG. 3A.

FIG. 4 is a rearwardly looking, exploded assembly view in perspectiveshowing component parts of the dryer of FIG. 1.

FIG. 4 A is a front view of a plenum portion of the dryer of FIG. 1

FIG. 4 B is a frontal view of portion of the dryer of FIG. 1. Thediffuser is mated with the plenum to form a T-shaped gas conditioningchamber. Flow apertures are formed on the diffuser.

FIG. 5 is a schematic view of a dryer and reflector drying the stent S.Illustrated in this schematic are streamlines of heated gas exiting thenozzle of the dryer of FIG. 1 and reflecting or being constrained toform an area of high pressure in the vicinity of the stent.

FIG. 6 is a schematic view of a dryer and gas expander drying the stentS. Illustrated in this schematic are streamlines of heated gas beingexpanded as the gas travels through the gas expander. The gas expanderacts as a partition that segregates the hot gas as it expands from thesurrounding cool gas and improves the uniformity of the gas propertiesin the vicinity of the stent.

FIG. 7A is a schematic view of gas flow controller for the dryer ofFIG. 1. The controller is configured for producing a constanttemperature gas flow into the dryer for variable and steady state flowrates.

FIG. 7B is a perspective view of a stent spraying and drying assemblyincorporating aspects of the disclosure.

FIGS. 8A-8C are perspective, side and a cross-sectional view of a spraynozzle according to another aspect of the disclosure. Thecross-sectional view is taken at section 8B-8B in FIG. 8C.

FIG. 9 is a prior art spray nozzle. The spray nozzle of FIGS. 8A-8C isan improvement over the spray nozzle of this figure. The spray nozzle ofFIG. 8 produces a more consistent atomized stream of adrug-polymer-solvent, and has less clogging than the prior art nozzle ofFIG. 9.

DETAILED DESCRIPTION OF EMBODIMENTS

According to a preferred implementation of the invention, a sprayer andheat nozzle is used to form a drug-eluting coat on a surface of a stent.A stent is an intravascular prosthesis that is delivered and implantedwithin a patient's vasculature or other bodily cavities and lumens by aballoon catheter for balloon expandable stents and by a catheter with anouter stent restraining sheath for self expanding stents. The structureof a stent is typically composed of scaffolding, substrate, or basematerial that includes a pattern or network of interconnectingstructural elements often referred to in the art as struts or bar arms.A stent typically has a plurality of cylindrical elements having aradial stiffness and struts connecting the cylindrical elements.Lengthwise the stent is supported mostly by only the flexural rigidityof slender-beam-like linking elements, which give the stent longitudinalflexibility. Examples of the structure and surface topology of medicaldevices such as a stent and catheter are disclosed by U.S. Pat. Nos.4,733,665, 4,800,882, 4,886,062, 5,514,154, 5,569,295, and 5,507,768.

As discussed earlier, one aspect of the stent coating process that hasbeen simplified, or improved, as a result of the dryer according to thedisclosure, is the ability to predict more consistently the rate ofsolvent removal and variation over the length of the stent of that rate.Increasing the predictability of a solvent's presence in the appliedcoating, or remaining when determining a final weight can greatlyincrease the ability and/or efficiency in which a predictable releaserate for a drug can be provided in a medical device, in the form of anapplied coating.

Moreover, as the design or desired loading of polymer-drug on the stentis determined from the measured weight, it will be readily appreciatedthat there needs to be an accurate, reliable and repeatable process forbeing able to determine the amount and distribution of solvent remainingover the length of the stent. This is especially true when less volatilesolvents are used, e.g., DMAc as opposed to the more volatile solventAcetone. Since it is expected that a greater percentage of solvent willremain after drying for solvents having higher boiling points, thecoating is more susceptible to variations in a solvent's presence overthe stent surface and/or across the coating thickness.

The disclosure provides examples of spraying/drying components suitedfor addressing the previously discussed drawbacks and limitations in theart pertaining to a drug-eluting coating applied via a drug-polymerdissolved in a solvent.

Dryer Assembly

FIG. 1 shows a perspective view of a dryer 1 according to one aspect ofthe disclosure. The dryer 1 may be included as a component used in astent coating process. Such a stent coating station implementing aprocess may include a sprayer, the dryer 1 and actuators for selectivelyplacing the sprayer and dryer over the stent between spraying and dryingsteps, respectively. Examples of a stent coating system that may adoptprinciples of the disclosure are described in U.S. patent applicationSer. Nos. 12/497,133; 12/027,947 and 11/764,006. In these examples, thedryer(s) and spray nozzle(s) described therein may use a dryer and spraynozzle according to the disclosure, as will be understood.

A coating process may be preprogrammed, or programmed on the fly toadjust parameters such as number of coats, or passes with the sprayerbetween drying steps, number of cycles of spraying and drying, etc.These and related parameters may be governed by the polymer-drug orsolvent used, type of stent or medical device being coated, e.g.,surface geometry. In particular embodiments the protocol for coating astent may be governed by a predetermined number of coating cycles, i.e.,spraying then drying, based on an analytically determined final coatingweight, or by intermittent weighing of the stent to determine the numberof cycles needed to arrive at the target coating weight.

The stent may be held in a mandrel and rotated as the sprayer applies adrug-polymer dissolved in a solvent, e.g., DMAc, to the surface of thestent. After one, two or more passes over the body of the stent with thesprayer, the dryer 1 is moved into position over the stent. The nozzleexit 3 is placed beneath the stent (or the stent moved into a dryingposition above the nozzle exit 3) at this stage of the process, so thatthe stent length extends lengthwise over the nozzle 3, i.e., parallel tothe direction measuring the length L in FIG. 1. Once in position, a massof heated gas exits from the nozzle exit 3 to accelerate theevaporation, or boiling-off of solvent from the coated stent surface. Ina preferred embodiment, this sprayer-dryer coating process is repeateduntil a final coating weight of drug-polymer and remaining solvent ismeasured. During each drying stage of preferred embodiments, the gasproduces a uniform heat transfer across the surface of 100 mm, 150 mm,and 200 mm stent. After a final coating weight has been reached, thestent may be placed in an oven for an extended period to removeadditional solvent.

As illustrated, the dryer's exit nozzle 3 is configured to produce themass of heated gas (represented by the array of vectors M_(g) extendingupward from the nozzle exit 3 in FIG. 1) over a linear length L, whichmay correspond to the length of the coated stent positioned for drying.FIG. 2B, which is a partial side cross-sectional view of dryer 1 takenat section 2B-2B in FIG. 2A, shows the stent S in position opposite thenozzle exit 3. The drying gas, e.g., heated nitrogen, is suppliedthrough a gas supply 2 b connected to a heater assembly 2. The heaterassembly 2 includes a tubular conduit with heating coils (not shown)exposed to the gas stream as it travels towards the plenum 10 (asrepresented by vector V_(∞) in FIG. 2B). The coils are connected to apower source via a power connection 2 a.

The gas traveling over the length of the heater assembly 2 is heated toa desired temperature and the gas pressure is known. Thus, gas enteringthe plenum 10 has a predetermined velocity and temperature (athermocouple may be placed near the entrance to measure gastemperature). The gas may be treated as an incompressible fluid betweenthe entrance 12 of the dryer 1 and exit 3. The velocity of gas passingthrough any cross-section, therefore, may be considered inverselyproportional to the size of the cross-section assuming no significantheat loss through the walls of the dryer (conservation of mass). In apreferred embodiment, the plenum, diffuser and nozzle portions of thedryer are made of PEEK plastic to minimize heat flow between theinterior of the dryer and exterior environment. PEEK may be used formaximum temperatures of up to 200 degrees Celsius.

FIG. 4 is a rearwardly-looking exploded view of the dryer 1 showing itscomponent parts, i.e., a plenum 10, a diffuser plate 50 and a nozzle 30.FIG. 3A is a forwardly-looking exploded view of the dryer 1 showingthese same components. Mounting blocks 11 a, 11 b are used to mount thedryer 1 to a support of a sprayer-dryer assembly, e.g., the spray-dryerassembly 350 of FIG. 7B, and a coupling or threaded sleeve 15 connectsthe heater assembly 2 to the dryer 1 entrance 12.

The diffuser 50, disposed, between the plenum 10 and nozzle 30, acts adivider between two distinct and functionally different chambers forconditioning the incoming gas. These are the plenum volume, space orchamber 14 and nozzle volume, space, or chamber 34 for flowconditioning. The assembly of the components may be described as theplenum 10 and diffuser 50 portions together forming a plenum chamber 14and the nozzle 30 and diffuser 50 portions together forming a nozzlechamber 34 for dryer 1. The diffuser 50 includes apertures 52 that maybe of the same diameter and evenly spaced over the length (seven areshown in FIG. 4) for passage of gas from the plenum chamber 14 to thenozzle chamber 34 after the gas has been first conditioned (as describebelow) by the plenum chamber 14. The gas mass M_(g) is then conditionedfor a second time in the nozzle chamber 34 before it exits the nozzleexit 3 from the nozzle chamber 34.

Plenum chamber 14 features are described with reference to FIGS. 2B, 4,4A and 4B. The plenum chamber 14 is generally T-shaped, formed by acavity 16 of the plenum 10 and the rear face 56 of the diffuser plate50. This chamber is sealed, with the exception of the upstreamcylindrical entrance passage 12 (incoming gas from heater assembly 12)and the downstream array of apertures 52 that provide a fluid passagebetween the plenum chamber 14 and the nozzle chamber 34.

An upper portion 16 b formed by the section extending from left to rightin FIG. 4A and preferably having the length L (see also FIG. 1) mateswith the diffuser plate 56 portion 56 b having the array of apertures52. A lower portion 16 a formed by the section containing the entrance12 mates with the diffuser portion 56 a that is devoid of an aperture oropening to the nozzle 34 chamber. Thus, when gas enters the plenumchamber 14 lower portion from the cylindrical opening 12, it isimmediately decelerated and gas pressure increases. This forces gasupwards into the expanded space of the plenum chamber 14. Gasaccumulated under this pressure in the upper portion 16 b then exitsfrom the plenum chamber 14 and enters the nozzle chamber 34 via thearray of apertures 52, which are arranged essentially over the samelength L as the exit nozzle 3, but with a larger opening (or total fluxarea) than the exits 40 at the nozzle 3.

In one embodiment the total flux area for gas flow through the aperturesis about 0.344 in², as compared to 0.0864 in² at the nozzle exit 3. Thetotal flux area at the inlet is about 0.196 in². The ratio of the inletto diffuser total flux area may be about 1:1.75, about 1:2 or betweenabout 1.5:1 and 2:1. The ratio of the diffuser to the exit total fluxarea may be about 4:1. In one embodiment, the ratio of the exit totalflux area (E) to the diffuser total flux area (D) to the inlet totalflux area (I), i.e., the quantity E:D:I, is between about 1:4:2 to1:4:2.5. In other embodiments, the diffuser total flux area is greaterthan the inlet total flux area and the inlet total flux area is greaterthan the nozzle exit channel total flux area.

Nozzle chamber 34 features are described with reference to FIGS. 2B, 3,3A and 4. As can be best appreciated in FIGS. 3 and 3A, the chamber 34is formed by mating the front face of the diffuser 50 with the nozzle 30so that surfaces 35 and 45 of the nozzle 30 abut the face of thediffuser 50 (FIG. 2B). The diffuser 30 has formed therein a cavity 36bounded by surfaces 35 and 45. At the upper end (near the nozzle exit 3)a linear array of nozzle exit channels 40 form rectangular notches 42over the length L of the cavity 36. When the cavity 36 is mated with theflat, opposing face of the diffuser 50, the channels 40 provide an arrayof rectangular passageways that produce a flow pattern having reducedturbulence, and more uniform gas flow from the nozzle chamber 34 outthrough the nozzle exit 3 along the length L.

Referring to FIGS. 2B, 3 and 3A, at the lower end of the chamber 34there is a relatively wide base portion, followed by a tapered portion.At the upper end of the tapered portion the chamber has its narrowestpoint, which is where lower, tapered ends 43 are formed to reduceturbulence and therefore noise at the nozzle exit 3 (as described ingreater detail below). The chamber 34 is therefore configured as aconverging channel extending upwards in FIG. 2B, and at a right angle tothe average gas flow direction through the apertures 52. That is, thegas flow makes a 90 degree turn upwards when it reaches the nozzlechamber 34. Pressure builds in the lower portion of the chamber 34, as aresult, then gradually reduces (as the section narrows) until the gasexits from the nozzle exit 3 where there is a sharp decrease in pressureto atmospheric pressure.

Referring to FIG. 3B, at the lower end of each of the channels 45 thereare sloped surfaces that form a converging point. Placed side by sidethe channels 40 having the tapered end 43 form a converging channel forgas flow traveling up from the lower portion of the chamber 34. It wasfound that by forming the tapered ends 43, or converging channelsleading to the exit 3, the flow tended to be more laminar at the exit.Additionally, vibrations presumably caused by oscillating gas flowemanating from the exits 40 was significantly reduced when the ends ofchannels 40 were tapered. As a result, there was a significant reductionin vibro-acoustic noise caused by the exiting gas mass M_(g). Thisreduced the noise that operators of a spray station would encounterduring operation.

In a preferred embodiment, the ratio of output length (L), i.e., lengthof array of channels openings 40 at exit 3, to the input diameter at theinlet 12 (D), to the height of the internal space from the plenumchamber 14 lower surface to exit 3 (H), to the depth from the leftmostwall of the nozzle chamber 34 in FIG. 2B to the rightmost wall of theplenum chamber 14 (2R), or the ratio L:D:H:2R is about 1: (1/10): (1/3):(1/8). Thus, for a length (L) of 100 mm, the depth of the gasconditioning chambers is about mm, the height of the gas conditioningchambers is about 33 mm and the diameter at the inlet is about 10 mm.

According to one embodiment of the dryer 1, which is configured fordrying a stent having a length of 200 mm, the length of the nozzle exitis preferably about 250 mm to ensure that the ends of the stent are notsubject to variations in the flow or influence by ambient air at theends of the nozzle, so called end effects. As explained in detail above,these values were obtained from results indicating the lengths of thenozzle exit relative to the stent length that would not produce aninconsistent or irregular rate of removal of solvent near the edges. Theverification of this minimal length was determined only through testing(if sensitive nature of remaining solvent's effect on release rate werenot a concern, of course one would prefer having the nozzle gas exitbeing more closer to stent length to conserve gas resources and increasedrying efficiency). In some embodiments the nozzle length may be about25% wider than the longest stent length suited for the dryer, so thatend effects are negligible. In other embodiments, the total length ofthe nozzle may be about 1.5 times the total length of the longest stentsuitable for the dryer, so that end effects, i.e., effect on solventirregularity and therefore release rate, are negligible.

According to a preferred embodiment, a dryer flow setting is 100standard liters/minute gas flow, and a temperature setting ofapproximately 100 to 120 degrees C.

Closed-Loop Controller

A gas flow rate through the heater assembly 2 in FIG. 1 may bemonitored/controlled by a commercially available mass flow regulator(not shown). For example, such a mass flow regulator may be used tooperate an adjustable valve coupling the gas supply line 2 b to a gassource to produce the desired flow rate. One example of a suitable massflow regulator is the Aalborg GFCS series mass flow regulator. A use ofa mass flow regulator and related control system suitable for use withaspects of the disclosure is described in U.S. application Ser. No.12/540,302.

During a coating process, the dryer is not in use when the stent isbeing coated. If the dryer is shut down or the flow rate reduced thetemperature of the gas at the entrance to the plenum 10 of the dryer 1will decrease. If the stent is moved into position above the nozzle exit3 for drying and the valve opened to increase the flow rate, there willbe a period of transient flow. It is desirable to avoid a period ofsolvent removal by transient gas flow, since the rate or amount ofsolvent removal by transient flow can be difficult to predict. It ispreferred, therefore, that the stent is dried only during steady stateflow conditions.

If gas flow at the dryer is instead maintained at a constant rate, thenthe temperature may be maintained. However, this wastes gas resources.It would be desirable if the gas flow rate could be reduced when thedryer is not in use while holding the gas temperature at a constantvalue.

To meet this need, a closed loop control is preferably implemented witha stent dryer system according to the disclosure, so that the gastemperature may be maintained at variable flow rates. Referring to FIG.7A, a schematic of this closed-loop control is illustrated. A controller300 continuously receives input temperatures at the entrance of theplenum from a thermocouple 302 and the gas flow rate upstream of theplenum entrance from a flow sensor 304. The controller 300 may beprogrammed to reduce the gas flow rate when the dryer is not in use, andincrease the gas flow rate when the stent is ready to be moved intoposition above the nozzle exit 3.

As the flow rate is adjusted by opening/closing the adjustable valve308, the controller senses a change in temperature from input receivedat the thermocouple 302, at which point it will increase/decrease thepower delivered to the heating coils by affecting control 306 for powerso that the temperature remains constant, regardless of the actual flowrate. Thus, according to this aspect of the disclosure, a dryer systemmay be operated at variable flow rates during a coating process whilemaintaining a substantially steady state gas flow during the dryingstage, or a minimal period of transient flow conditions until a steadystate condition is reached. This improves/maintains the predictabilityof solvent removal during drying, minimizes down time and allows gasresources to be conserved. The coated stent is almost immediatelysubject to the drying step and dried in a manner that allows theimproved prediction of solvent removal. As discussed earlier, this is acritical step in the process of producing a predictable release rate fora drug-eluting stent and accurate assessment of whether the desireddrug-polymer coating weight has been reached.

A closed loop controller in accordance with the foregoing may beincorporated into a spray-dryer assembly of the type described in U.S.application Ser. No. 12/540,302. FIG. 7B is a reproduction of FIG. 3A ofthis application. In this assembly 350, a pair of stents on mandrels(not shown) are supported from right-side spindle assemblies 360(spindles 362), which are disposed on respective left and right sides ofa spray isolator enclosure 352. According to this configuration, a pairof supported stents on one side of the spray isolator enclosure 352 aredried while a pair of stents supported on the opposite side of the spraychamber 352 are sprayed. The spindle assemblies 360 rotate the stentsduring drying and spraying. A spray nozzle 400 is shown disposed withinthe chamber. When moved into, or out of the spray isolator enclosure 352the stents on mandrels are passed through openings 364. A left and rightpair of dryer nozzles (each being the nozzle 30 of dryer 1) are showndisposed between the respective left-side and right-side spindleassemblies 360 in FIG. 7B and the spray isolator enclosure 352 (only oneof these left and right pairs of nozzles 30, respectively, is visible inthis view). The stents are dried in area 363.

One of a pair of left and right stents may be sprayed and dried usingthe controller 300 assembly 350 according to the following steps. First,the stents are placed within the spray isolator enclosure 352 forspraying. During, or prior to the spraying, the gas flow to the nozzles30 is set at an idle setting with the controller increasing the power tothe heating coils as necessary (based on input received from thethermocouple 302) until the temperature of the gas flow reaches a steadystate condition. A transducer 354, mounted on a spindle assembly 360,may also be used to measure the exit temperature above the nozzle.

After, or just prior to completion of an application of coating materialon the stents using the nozzle 400, the controller 300 increases the gasflow temperature to the drying gas flow rate. While the gas flow isbeing increased, the controller 300 monitors the temperature at theplenum entrance 12 by input received from the thermocouple 302 and thepower decreased to the heating coils as necessary to maintain thetemperature of the exiting gas flow. Once the gas flow has reached theoperating flow rate and temperature, the stents are moved into thedrying area 363. The stents are rotated by a rotation mechanism builtinto the spindle assembly 360. After drying is complete the gas flow isagain returned to the idle position and the power to the heating coilsincreased as necessary to maintain the same gas flow temperature (basedon input received from the thermocouple 302). The process repeats untilthe desired coating weight is obtained.

Reflector and Expander Embodiments

According to another aspect of the disclosure a dryer includes structureexternal to the dryer nozzle exit 3 to control or effect the interactionbetween ambient air and gas exiting the dryer and surrounding the stent.As will be appreciated, when gas exits the nozzle at high velocitiesthere is a corresponding drop in pressure, which causes the ambient airto be drawn in towards the nozzle exit and stent surface and mix withthe hot gas. As a result, the cooler ambient air draws heat away fromthe hot gas exiting the nozzle and reduces the efficiency of the hot gasto remove solvent.

In one embodiment, a dryer is configured in combination with a reflectorto redirect or focus gas passing by the stent S back towards the stentto increase the efficiency of the hot gas to evaporate or boil offsolvent from the stent surface. FIG. 5 illustrates the stent S disposedbetween a curved reflector 120, e.g., parabolic or semicircular, and thedryer 1, and the circulation of hot gas around the stent and reflectedby the reflector surface 122. In the region between the reflector 120and the stent S the gas pressure is increased. As a result, the coolerambient air mixes less with the hot gas and draws less heat away fromthe gas passing by the stent.

In another embodiment, a gas expander 140 is fitted over the nozzle exitto shield or insulate the hot gas exiting from the dryer from the coolerambient air, as depicted in FIG. 6. As the gas exits the nozzle itexpands as it travels through the expansion space formed by expander140. This increases the gas pressure surrounding the stent, therebycausing less heat loss before the gas reaches the stent surface. Thehigher pressure also serves to maintain the uniformity of gas in thevicinity of the stent. This is depicted in FIG. 6 by the turbulentmixture of ambient air and hot gas that forms in areas away from thestent surface. The stent may be placed near, partially within or fullywithin the expander 140.

In some embodiments the gas expander may be sized based on the diameterof the stent, as depicted in FIG. 6. The stent's diameter D is shown.The width of the mouth, and height of the expander section are both 4D,or about four times the stent diameter. And the stent is sunken into theexpansion chamber by about 1 D, as illustrated. In other embodiments themouth may be less than 4D while the height is the same. In oneembodiment, the mouth is 2D while the height is 4D. It is believed thatthe more narrow mouth according to this embodiment will produce a moreuniform gas temperature and velocity about the stent, while making theplacement within the expander during a high volume coating/dryingprocess easy to implement, or without other drawbacks resulting from amore narrow mouth, as will be appreciated. preferably, however, themouth diameter is 4D.

In some embodiments the stent may be placed closer, or further from thenozzle exit 3. If the stent is placed too close to the nozzle exit 3,the distance between the leading edge of the stent and exit may createan uneven flow condition, which can cause the stent to be jostled about.In other embodiments the stent may be moved further than 3D from thenozzle but within the mouth. A stent placed outside of the mouth may notbenefit as much from the environment provided by the gas expander. Inthose cases the ambient air may interfere with the velocity andtemperature near the stent surface, thereby producing more unpredictableresults or loss of drying efficiency. It is believed that an optimalefficiency and uniformity may be achieved when the stent is placed 1Dwithin the mouth, 3D from the nozzle, and the gas expander mouth andheight are respectively, 4D and 4D. In some embodiments the stent isplaced at 75% of the mouth distance from the nozzle and the ratio ofwidth to height is 1:1. It was found that with this condition,uniformity of solvent removal was maintained, or indeed improved andefficiency of solvent removal improved. Further, as mentioned earlier,in some embodiments the optimal distance may be found from the solutionto the optimization constrained by three variables: (1) expander design,(2) heat transfer associated with gas and surrounding environment and(3) the type of stent support used.

Spray Nozzle

According to another aspect of the disclosure a spray nozzle ismanufactured to reduce clogging and improve consistency of adrug-polymer dissolved in a solvent.

Referring to FIG. 9, a prior art spray nozzle 200 is shown. The nozzle200 is an atomizing spray nozzle that may be used to produce a conicalspray pattern of an atomized solution of a fluid. The nozzle may use aconstant airflow with pulsed delivery to produce the atomized spraypattern. A prior art spray nozzle suitable for this use is the Sonicair™nozzle available from the IVEK Corporation™, 10 Fairbanks Rd. NorthSpringfield, Vt. 05150 USA.

The nozzle 200 includes a housing 201 having a first bore formed toreceive a cannulae 220, which carries the fluid to the nozzle tip 203,and a third and fourth bore 210 and 214 which provides a conduit forpressurized gas used to atomize the fluid at the tip 203. A threading isprovided at the opposite end for connecting a liquid supply line 220Aand gas supply line 210A.

At the exit 203 a nozzle cap 213 having a centrally located orifice,sized according to the desired droplet size in the spray pattern, isplaced over the exit hole 202 of the cannulae 220, which is in fluidcommunication with a chamber 215 in fluid communication with pressurizedgas conduits 210, 214.

It was discovered that drug-polymer coatings applied using the nozzle200 produced unacceptable variations in spray patterns and frequentclogging. Certain modifications (as described below) were made to thenozzle in the hopes that these problems could be eliminated.

Surprisingly and unexpectedly, it was found that a much improved spraypattern and less frequent clogging occurred when these modificationswere implemented.

When it was discovered that the coating process could be significantlyimproved overall by improving upon the nozzle, attempts were made toimprove on the existing prior art nozzle by polishing interior andexterior surfaces proximal the nozzle orifice. It was discovered duringtests using a particular polymer-drug-solvent solution, e.g., 93%solvent and 7% drug-polymer, and desired conical spray pattern that theexiting prior art nozzle contained several shortcomings. In short, forthe particular application of a drug-polymer coating according to oneaspect of the invention it was discovered that the commercial nozzle, anexample of which is provided here, although designed to produce preciseand consistent spray patterns for applying a drug-eluting coating tomedical devices and, in particular, stents, fell well short of therequirements for a drug-eluting coating having the required tolerance inthe coating weight and distribution needed to achieve the objects of thedisclosure, as previously discussed.

Two aspects of the nozzle that were found to produce inconsistentresults were manufacture by an EDM process and nozzle-to-nozzlevariations due to tolerances for parts during manufacture being toolarge. Polishing inner and outer areas proximal the nozzle orifice, forexample, was not enough by itself to solve the problems. Nor wasswitching to a different design of sprayer. For example, anultrasonic-type nozzle was tested. This alternative did not improveresults as non-uniform and inconsistent coatings were found on a stentsprayed using an ultrasonic-type nozzle.

FIG. 8A illustrates a perspective view of an improved spray nozzle 400according to the disclosure. FIG. 8C shows a side view of this nozzleand FIG. 8B shows a cross-sectional view of the nozzle 400 taken atsection 8B-8B of FIG. 8C. The nozzle has a housing 401 which has amodified bore for receiving a modified cannulae 420, bores 410, 412 forpassage of pressurized air and an exit end 403. A nozzle cap 413 islocated at the nozzle end 403. The atomized drug-polymer-solventsolution exits from a modified orifice 401 a.

Some of the important features of the nozzle of FIG. 8 that differ fromthe prior art nozzle of FIG. 9 are the finishing on the fluid surfaces,material, smoothness and consistency of the orifice hole and tighttolerances enforced in the nozzle passages.

The first improvement was in the use of different material. The housing401 is made from 17-4 PH 900 heat treated steel whereas the cannulae 420is made from 316 stainless steel. The nozzle 200, in contrast, is madefrom 316 stainless steel throughout. By using different materials innozzle 400 having a different hardness, there is a tighter control ofthe press fit between the cannulae 420 and housing 401. Moreover,galling between the housing 401 and cannulae 420 is eliminated due tothe different material, i.e., the 316 steel being a softer metal thanthe 17-4 PH 900 heat treated steel.

The second improvement was in the formation of the orifice of the endcap. The nozzle 200 end cap 213 is formed by a standard edge break onthe inside and outside edges of the tapered orifice. This producedmachining marks and variations around the orifice contributing to aninconsistent spray pattern (a result of an EDM manufacturing process).The end cap 413 for the nozzle 400 was instead made with more precisetolerance control. Additionally, surfaces on the inside and outside ofthe orifice were polished to produce more uniform surfaces for passageof the atomized fluid through the orifice (the end of the cannulaefacing the orifice was also polished). These improvements in the nozzlecap 413 reduced instances of clogging, and produced a more uniform spraypattern as compared to the nozzle 200 end cap 213.

A third improvement was made in the cannulae. First, the cannulae wasmade with a stepped outer diameter for precise placement against a ledge420A formed in the receiving bore of the housing. Mating with a steppeddiameter bore also prevented the cannulae 420 from being pushed into theend cap 413 when the fluid supply fitting is secured at the connection420A. The cannulae 220, by contrast, is formed as a constant diametercylinder and received in a corresponding constant diameter bore. Thisassembly makes placement of the cannulae 220 within the bore lessprecise and the fit less snug.

Second, the cannulae 420 bore is made larger and steps down to a smallerdiameter bore, which reduces the pressure drop along the length of thecannulae 420. The cannulae 220 of the nozzle 200 has instead a constantbore. By reducing the pressure drop there is a more consistent supply offluid at the desired pressure, which contributes to a more consistentspray pattern.

A fourth improvement in nozzle performance relates to a method ofreducing instances of clogging, particular between spraying intervals,i.e., when the stent is moved to the dryer. A buildup prevention methodfor a nozzle includes a secondary nozzle having its nozzle orientatedtowards, and at an angle of about 20-40 degrees relative to the nozzlecap 413 lower face. This nozzle delivers a steady stream of gas, e.g.,Nitrogen gas, towards the orifice 401 a between each spraying step. Byapplying this steady stream of gas a buildup of drug-polymer solution isforcibly blown off the orifice of the spray nozzle as the nozzle restsbetween spray cycles. Simultaneous with this applied gas is asufficiently high pressure being maintained through the atomizing gaspressure source. This should prevent any buildup of drug-polymersolution from being blown into the bore of the cannulae 422 due to thesecondary nozzle drying gas. In one embodiment, the 20-40 orientateddrying gas was delivered at an exit pressure of 5-20 psi for about 1-3seconds. The balancing pressure of the atomizing gas may be the same asthe operating pressure, e.g., the recommended operating pressure for theSonicair™ nozzle. According to this aspect of the disclosure, a stentdrying and spraying process includes a spray nozzle drying stepintermittent to spraying steps.

Although the above embodiments have been described in connection with astent, it is to be understood that the present invention can be appliedto devices other than stents. Medical devices to which this inventionmay be adapted for use includes balloon expandable stents,self-expanding stents, grafts, stent-grafts, balloons, and catheters.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

What is claimed is:
 1. A dryer having an inlet conduit supplying anincoming gas stream and an exit area that produces a drying gas,comprising: a first gas conditioning chamber and a second gasconditioning chamber together forming a closed space for theconditioning of a gas supplied by a gas source and discharged at anozzle exit, the gas having a mass flow rate that is the same at thenozzle exit as the mass flow rate supplied by the gas source during asteady state flow condition; the first gas conditioning chamberincluding a circular inlet coupled to the gas source and a linear arrayof apertures downstream of the circular inlet; and the second gasconditioning chamber including the linear array of apertures and anarray of nozzle exit channels downstream of the linear array ofapertures; wherein the dryer is adapted for producing a substantiallyuniform drying air mass from the linear array of nozzle exit channels.2. The dryer of claim 1, wherein the circular inlet has a diameter, thearray of nozzle exit channels extends over a nozzle length, the inlet isspaced from the array of nozzles exits by a first length spanning boththe first and second gas conditioning chamber, and the central axis ofthe circular inlet is separated from the opening of the nozzle formed bythe linear array of nozzle exit channels by a second length, wherein thenozzle length is at least five times larger than the inlet diameter, thenozzle length is at least twice as large as either the first length andthe second length, and the dryer as adapted for producing asubstantially uniform drying air mass over the linear array of nozzleexit channels at the rate of 100 standard liters/minute nitrogen gas ata temperature of approximately 100 to 120 degrees C.
 3. The dryer ofclaim 2, wherein the dryer configured such that gas entering the inlethas a first mean flow direction, the gas entering the first gasconditioning chamber has a second mean flow direction, and the gasexiting the dryer from the linear array of nozzle exit channels has athird mean flow direction, wherein the first mean flow direction isperpendicular to the second mean flow direction and the third mean flowdirection is perpendicular to the second mean flow direction and thefirst mean flow directions.
 4. The dryer of claim 3, wherein first gasconditioning chamber is further configured such that gas has the thirdmean flow direction before the second mean flow direction.
 5. The dryerof claim 4, wherein the linear array of apertures are configured suchthat the gas has the first mean flow direction when it leaves the firstgas conditioning chamber and enters the second gas conditioning chamber.6. The dryer of claim 1, wherein the mean flow direction through thecircular inlet is perpendicular to the mean flow direction for gasentering the first gas conditioning chamber.
 7. The dryer of claim 6,wherein the first gas conditioning chamber includes a first sectionincluding a circular opening, a wall opposite the circular opening andthree adjoining walls such that the gas is forced to make a right angleturn upwards when it enters the first section.
 8. The dryer of claim 7,wherein the gas the first gas conditioning chamber includes a secondsection having a side including an opening for receiving the gas fromthe first section, the side forming a portion of a cavity that extendslengthwise and parallel to the array of apertures, the array ofapertures forming one of the walls and running parallel to the secondsection and the array of nozzle exit apertures.
 9. The dryer of claim 8,wherein the first gas conditioning chamber is T-shaped.
 10. The dryer ofclaim 9, wherein the larger length of the T-shaped section is about thesame length as the length spanned by the linear array of nozzle exitchannels.
 11. The dryer of claim 1, wherein the second gas conditioningchamber has an upstream portion and a downstream portion, and anintermediate portion between the upstream and downstream portions, theintermediate portion being tapered so that flow there through isaccelerated before reaching the downstream portion.
 12. The dryer ofclaim 11, wherein the second gas conditioning chamber has a mean flowdirection that is perpendicular to a mean flow direction for gassupplied through the circular inlet.
 13. The dryer of claim 1, whereinturbulence and noise-reducing vanes are formed at the upstream ends ofthe nozzle exit channels
 14. The dryer of claim 13, wherein the lineararray of nozzle exit channels form square openings.
 15. The dryer ofclaim 13, wherein the nozzle exit channels are configured such that gaspassing through the channels and exiting from the nozzle issubstantially laminar flow.
 16. The dryer of claim 13, wherein the noisereducing vanes are adapted for reducing the amplitude or degree of fluidoscillations at the nozzle exit.
 17. The dryer of claim 1, furtherincluding a gas expander disposed about the linear array of nozzle exitnozzle channels.
 18. The dryer of claim 17, the gas expander including aparabolic or conical skirt that diverges outwardly from the nozzle exitsuch that the hot gas is segregated from the surrounding ambient gas asit travels through the parabolic or conical skirt.
 19. The dryer ofclaim 18, the gas expander being configured for insulating exit gasesfrom ambient air until the pressure of the gas builds up sufficiently tominimize substantial heat loss near the nozzle exit.
 20. The dryer ofclaim 1, further including a gas reflector disposed opposite the lineararray of nozzle exit channels.
 21. The dryer of claim 20, wherein thereflector is a semi-circular or parabolic surface configured for forminga high pressure region of hot gas for a stent disposed between thereflector and nozzle exit.
 22. A method for removing a solvent from astent, comprising the steps of rotating the stent above a nozzle exitportion of a dryer to cause a gas produced by the dryer to effect aremoval rate of solvent from the stent, the gas being produced by thefollowing steps: supplying a gas to the dryer, the gas being deliveredthrough a circular conduit such that the gas has an input mean flowdirection into the dryer, decelerating the gas as it encounters a firstchamber of the dryer, the first chamber presenting the gas with a firstenlarged space arranged such that the gas is expanded in a directionperpendicular to the input mean flow direction, after the gas has beenexpanded in a direction perpendicular to the input mean flow direction,accelerating the expanded gas by forcing the gas through a linear arrayof apertures arranged in the direction perpendicular to the mean flowdirection, the gas entering a second chamber, and decelerating, and thenaccelerating the gas as it fills the second chamber, the second chamberpresenting the gas with a second enlarged space, followed by a narrowedspace downstream of the second enlarged space and the nozzle exitdownstream of the narrowed space; wherein the gas produces a uniformheat transfer from the gas to the stent over the entire surface of therotating stent.
 23. The method of claim 22, wherein the decelerating thegas as it encounters a first chamber of the dryer includes the step ofredirecting the flow abruptly 90 degrees and forcing it into arectangular area formed in part by a wall comprising the linear array ofapertures.
 24. The method of claim 23, wherein the rectangular area isarranged lengthwise and parallel to the array of nozzle exit channels.25. The method of claim 22, further including the step of conditioningthe flow at the nozzle exit portion, including the steps of convertingthe flow to a substantially laminar flow having substantially parallelstreamlines when exiting the nozzle exit portion.
 26. The method ofclaim 25, further including the step of forcing the gas through vanesconfigured for aligning the mean flow direction with the direction inwhich exit channels leading to a nozzle exit opening extend.
 27. Themethod of claim 25, further including the step of reducing vibrations atthe nozzle exit caused by oscillations normal to the mean flow directionby forcing gas through upstream vanes.
 28. The method of claim 22,wherein the input flow properties are nitrogen gas at 100 liters/min andbetween about 100 and 120 degrees Celsius.
 29. An apparatus for coatinga stent, comprising a sprayer for applying a coating to a surface of thestent; a dryer configured to remove a controlled percentage of solventfrom a surface of the stent using a stream of gas supplied by the gassupply, the dryer including a nozzle, the dryer further comprising: afirst gas conditioning chamber and a second gas conditioning chambertogether forming a sealed space for the conditioning of a gas receivedfrom a gas source and discharged at a nozzle head, the mass flow ratesupplied by the gas source being the same as the mass flow rate at thenozzle head during a steady state flow condition, the first gasconditioning chamber including a circular inlet coupled to the gassource and a linear array of apertures located downstream of thecircular inlet, and the second gas conditioning chamber including thelinear array of apertures and a line of nozzle exit channels downstreamof the linear array of apertures; wherein the first gas conditioningchamber and the second gas conditioning chamber cooperate to convert gasreceived at the circular inlet to a gas stream having uniform velocityand temperature at the nozzle exit; a gas supply; a control system forcontrolling the rate at which gas is supplied to the dryer andtemperature of the gas exiting the dryer such that the gas temperatureis maintained at a constant temperature for variable gas flow rates; anda mechanism for transporting the stent and mandrel to and from the dryerand sprayer.
 30. The apparatus of claim 29, wherein the control systemincludes a control logic for adjusting flow parameters based on inputreceived from a thermocouple adapted for producing a signal reflecting achange in temperature of the gas flow before it enters the dryer. 31.The apparatus of claim 30, wherein the control system further includes acontrol logic for adjusting heat supplied to the gas stream in responseto a signal received from the thermo-couple.
 32. The apparatus of claim31, wherein the control system further includes a control logic foradjusting the mass flow rate, such that the control system is adaptedfor adjusting the heat and flow rate of the gas stream to produce aconstant temperature gas stream at variable flow rates.
 33. A method forcoating a stent, the stent being movable between a sprayer and a dryer,comprising the steps of producing a steady state first mass flow rate ofa drying gas from a nozzle exit of the dryer including the steps ofopening a valve and adjusting a heater for heating the gas in responseto a sensed change in the gas temperature; spraying adrug-polymer-solvent on a surface of the stent while the first mass flowrate steady state condition exists at the nozzle exit; before, orshortly after completing the application of a first coat of thedrug-polymer-solvent on the stent, increasing the mass flow rate to thedryer while maintaining the same temperature including the step ofadjusting the heater in response to a sensed change in the gastemperature, the dryer producing a stead state second mass flow rate;moving the stent to the dryer, or the dryer to the stent, and drying thestent using the gas exiting the dryer at the steady state second massflow rate, wherein the second mass flow rate is characterized by auniform, linear heat transfer from the gas to the stent surface suchthat a correspondingly uniform rate of solvent removal occurs on thestent surface, and the steady state temperature of the gas for the firstmass flow rate is substantially the same as the steady state temperatureof the gas for the second mass flow rate.
 34. The method of claim 22,wherein the input flow properties are nitrogen gas at 100 liters/min andbetween about 100 and 120 degrees Celsius.
 35. A method of making aspray nozzle, comprising: forming a housing from a first metal having afirst hardness, the housing including a first bore for the passage of anatomizing gas and a second bore for receiving cannulae, the second borehaving a first and second diameter, the first diameter forming at itsupper end a ledge; forming a cannulae from of a second metal, the secondmetal having a second hardness, less than the first hardness, thecannulae including a tapered bore for receiving fluid, such that thetapered bore reduces a pressure drop for fluid disposed within thetapered bore a stepped outer diameter, and a polished lower end; forminga polished nozzle cap that is devoid of scratches or abrasions on itsinner and outer surface near a nozzle orifice; press-fitting thecannulae into the second bore such that the stepped outer diameter isplaced against the ledge of the housing bore; and fitting the nozzle ata nozzle exit so that the orifice is aligned with an exit aperture ofthe cannulae.
 36. A method for coating a stent with a drug-polymersolution, comprising: spraying the stent using a spray nozzle, includingthe steps of delivering a first metered supply of an atomizing gasthrough a first bore in fluid communication with a nozzle orifice, and adrug-polymer solvent fluid through a second bore in fluid communicationwith the nozzle orifice; after spraying the stent, moving the stent to adryer for drying the stent; and while the stent is being dried, applyinga second metered supply of a gas to the nozzle, the second meteredsupply being different from the first metered supply, wherein the secondmetered supply is adapted to reduce instances of clogging or buildup ofdrug-polymer solvent proximal the nozzle orifice when the stent is beingdried.
 37. The method of claim 36, wherein the step of while the stentis being dried, applying a second metered supply of a gas to the nozzle,the second metered supply being different from the first metered supply,further includes disposing a second source of pressured gas, externalthe nozzle, adjacent the nozzle and directed towards the nozzle, andapplying the second metered supply of gas to the nozzle while a thirdmetered supply of gas is applied to the nozzle by way of the secondsource of pressurized gas.
 38. The method of claim 37, wherein the stepof disposing a second source of pressured gas, external the nozzle,adjacent the nozzle and directed towards the nozzle includes disposing asecond nozzle having a orifice orientated to direct a stream of gastowards the orifice of the nozzle at an angle of between 20-40 degreesrelative to a lower face of the nozzle.
 39. The method of claim 36,wherein the coating applied to the stent is solution of about 93%solvent and about 7% drug-polymer solution.
 40. The method of claim 39,wherein the solvent is DMAc.
 41. The dryer of claim 1, wherein the ratioof the total flux area for the array apertures to the nozzle exitchannels is about 4:1.
 42. The dryer of claim 1, wherein the ratio ofthe total flux area for the array apertures to the inlet may be about1.75:1 or 2:1.
 43. The dryer of claim 1, wherein the ratio of the totalflux area for the nozzle exit channels to the inlet flux area is about2:1.
 44. The dryer of claim 1, wherein the array of nozzle exit channelshave a length L, the depth of the combined chambers between inlet andexit is D, the height of the combined chambers between inlet and exit isH and the size of the diameter at the inlet is 2R, wherein the ratio ofL to D, to H to 2R (L:D:H:2R) is about 1:(1/10):(1/3):(1/8); the ratioof L:2R is about 1:8; the ratio of L:D is about 1:1/10; or the ratio ofL:H is about 1:1/3; and wherein the dryer is capable of producing auniform temperature and velocity suitable for drying a stent for a flowrate of about 100 liters/min at a temperature in the range of 100 to 120degrees Celsius.
 45. The dryer of claim 1, wherein the length of thearray of nozzle channels is have a length that is about 125% of thelength of a stent, or 1.5 times the length of a stent length for whichthe dryer is configured for drying to produce a uniform heat transferfrom the gas to the stent surface.
 46. The method of claim 33, whereinthe dryer has a linear array of exit channels having a length that is125% or 1.5 times the length of the stent in order to avoid producingvariations in the drug-eluting properties of the stent near the edges.47. The dryer of claim 17, wherein the gas expander is sized such thatit has a height, mouth, or depth of insertion of a stent size that isabout a multiple of the diameter of the stent.
 48. The dryer of claim47, wherein the gas expander is configured for maintaining a uniformheat transfer near the stent surface, the stent having a diameter D,wherein the height of the expander is about four times D, the mouth ofthe diameter is between two times and four times D, and the stent isplaced about a D distance from the mouth.
 49. The apparatus of claim 29,further including a gas expander having a height to mouth ratio of 1:1.50. The apparatus of claim 29, wherein the mechanism is configured forplacing the stent within about one stent diameter within the gasexpander, or about 25% of the height from the mouth.
 51. A method ofdrying a stent, comprising the steps of dryer having an inlet conduitsupplying an incoming gas stream and an exit area that produces a dryinggas, comprising: placing the stent near an array of nozzle exitchannels; and placing the stent within a gas expander such that thestent is between a mouth of the expander and the array of nozzle exitchannels; wherein the dryer is adapted for producing a substantiallyuniform drying air mass from the linear array of nozzle exit channels.52. The method of claim 47, wherein the stent has a diameter and thestent is placed within one diameter of the mouth.